Due to continued advances in genetic and cell engineering technologies, proteins known to exhibit various pharmacological actions in vivo are capable of production in large amounts for pharmaceutical applications. However, one of the most challenging tasks in the development of protein pharmaceuticals is to deal with the inherent physical and chemical instabilities of such proteins, especially in aqueous dosage forms. To try to understand and maximize the stability of protein pharmaceuticals and any other usable proteins, many studies have been conducted, especially in the past two decades. These studies have covered many areas, including protein folding and unfolding/denaturation, mechanisms of chemical and physical instabilities of proteins, as well as various means of stabilizing proteins in aqueous form; see, e.g., Manning et al., Pharm Res., 1989; 6:903-918; Arakawa et al., Adv Drug Deliv Rev., 2001; 46:307-326; Wang W., Int J. Pharm., 1999; 185:129-188; Chen T., Drug Dev Ind Pharm., 1992; 18:1311-1354, and references cited therein.
Because of the instability issues associated with the aqueous dosage forms, powder formulations are generally preferred to achieve sufficient stability for the desired shelf life of the product. Various techniques to prepare dry powders have been known, substantiated and practiced in the pharmaceutical and biotech industry. Such techniques include lyophilization, spray-drying, spray-freeze drying, bulk crystallization, vacuum drying, and foam drying. Lyophilization (freeze-drying) is often a preferred method used to prepare dry powders (lyophilizates) containing proteins. Various methods of lyophilization are well known to those skilled in the art; see, e.g., Pikal M J., In: Cleland J L, Langer R. eds. Formulation and Delivery of Proteins and Peptides. Washington, D.C.: American Chemical Society; 1994:120-133; Wang W., Int J. Pharm. 2000; 203:1-60, and references cited therein.
The lyophilization process consists of three stages: freezing, primary drying, and secondary drying. Because the protein product is maintained frozen throughout the drying process, lyophilization provides the following advantages over alternative techniques: minimum damage and loss of activity in delicate, heat-liable materials; speed and completeness of rehydration; the possibility of accurate, clean dosing into final product containers so that particulate and bacterial contamination is reduced; permits product reconstitution at a higher concentration than it was at the time of freezing; and permits storage of the product at ambient temperatures. The latter can be particularly useful for hospital products in areas that do not have ready access to freezers, especially ultra-cold freezers.
Unfortunately, even in solid dosage forms, some proteins can be relatively unstable and this instability may be a product of the lyophilization method used for preparing the solid dosage forms and/or the inherent instability of the actual solid dosage formulations themselves. For example, in certain instances, lyophilization processing events can force a protein to undergo significant chemical and physical changes. Such processing events include concentration of salts, precipitation, crystallization, chemical reactions, shear, pH, amount of residual moisture remaining after freeze-drying, and the like. Such chemical and physical changes include, e.g., formation of dimer or other higher order aggregates, and unfolding of tertiary structure. Unfortunately, these changes may result in loss of activity of the protein, or may result in significant portions of the active materials in the drug having been chemically transformed into a degradation product or products which may actually comprise an antagonist for the drug or which may give rise to adverse side effects. In addition to the instabilities incurred upon proteins because of the inherent steps of the lyophilization process, other disadvantages of lyophilization include: long and complex processing times; high energy costs; and expensive set up and maintenance of the lyophilization facilities. As such, use of lyophilization is usually restricted to delicate, heat-sensitive materials of high value. Additionally, lyophilized powders are typically formed as cakes, which require additional grinding and milling and optionally sieving processing steps to provide flowing powders. To try to understand and to optimize protein stability during lyophilization and after lyophilization, many studies have been conducted; see, e.g., Gomez G. et al., Pharm Res. 2001; 18:90-97; Strambini G B., Gabellieri E., Biophys J., 1996; 70:971-976; Chang B S. et al., J Pharm Sci., 1996; 85:1325-1330, Pikal M J., Biopharm, 1990; 3:9, Izutsu K. et al, Pharm. Res, 1994; 11-995, Overcashier D E., J Pharm Sci., 1999; 88:688, Schmidt E A. et al., J Pharm Sci., 1999; 88:291, and references cited therein.
In order to allow for parenteral administration of these powdered drugs, the drugs must first be placed in liquid form. To this end, the drugs are mixed or reconstituted with a diluent before being delivered parenterally to a patient. The reconstitution procedure must be performed under sterile conditions, and in some procedures for reconstituting, maintaining sterile conditions is difficult. One way of reconstituting a powdered drug is to inject a liquid diluent directly into a drug vial containing the powdered drug. This can be performed by use of a combination-syringe and syringe needle having diluent contained therein and drug vials which include a pierceable rubber stopper. The method of administration goes as follows: 1) the rubber stopper of the drug vial is pierced by the needle and the liquid in the syringe injected into the vial; 2) the vial is shaken to mix the powdered drug with the liquid; 3) after the liquid and drug are thoroughly mixed, a measured amount of the reconstituted drug is then drawn into the syringe; 4) the syringe is then withdrawn from the vial and the drug then be injected into the patient.
For people requiring frequent parenteral administration of drugs, it is common practice for those people to be provided with home-use kits which may include injection cartridges, pre-filled syringes, pen injectors and/or autoinjectors to be used for the purpose of self-administration. Autoinjectors incorporating needled injection mechanisms are well known and thought to exhibit several advantages relative to simple hypodermic syringes. Such needled autoinjectors generally include a body or housing, a needled syringe or similar device, and one or more drive mechanisms for inserting a needle into the tissue of the subject and delivering a desired dose of liquid medicament through the inserted needle. To date, all known autoinjector devices have been used with liquid formulations. There still exists a need for an autoinjector that can be used to deliver powdered formulations.
Other methods of administration of powdered drugs include the use of dual-chambered injection cartridges and/or pre-filled syringe systems. Injection cartridges of the dual-chamber type are well-known and have found a wide use. They are used together with various types of injection apparatuses which serve to hold the cartridge as it is readied for injection and as injections are subsequently administered. Injection cartridges of the dual-chamber type generally comprise a cylindrical barrel, which is shaped like a bottleneck at its front end and has an open rear end. The front end is closed by a septum of rubber or other suitable material, which is secured in place by means of a capsule. This capsule has a central opening where the septum is exposed and may be pierced by a hollow needle to establish a connection with the interior of the cartridge; see e.g., U.S. Pat. No. 5,435,076 and references cited therein.
Dual-chambered pre-filled syringe systems are well known and have found wide commercial use; see e.g., U.S. Pat. Nos. 5,080,649; 5,833,653; 6,419,656; 5,817,056; 5,489,266, and references cited therein. Pre-filled syringes of the dual-chambered type generally comprise an active ingredient which is lyophilized in one chamber, while a second chamber of the syringe contains a solvent that is mixed with the active substance immediately before application. In such devices, in order to facilitate the movement of the syringe plunger against compression of air, the chamber containing the lyophilized product typically has large head space and some additional mechanism, e.g., rotation of the plunger, screwing in the plunger, is necessary. As a result, the reconstituted drug needs to primed to remove large volumes of air prior to injection; see e.g., U.S. Pat. No. 6,817,987 which describes a hypodermic syringe which holds a solvent and a soluble component (medicament) and wherein the solvent and medicament are mixed as the user presses and then releases the plunger of the syringe. Upon complete mixing, the user attaches a needle and then rotates the plunger of the syringe to allow for the injection.
Several syringe devices of various configurations and various processes of lyophilization have been described in, e.g., U.S. Pat. Nos. 5,752,940; 5,876,372; 6,149,628; 6,440,101, and references cited therein. Importantly, in each instance, the devices comprise multiple parts and require at least a two step, two directional reconstitution process for the delivery of the lyophilized powdered drug. Other devices used for reconstitution and delivery of powdered drugs are described in, e.g., U.S. Pat. Nos. 4,328,802; 4,410,321; 4,411,662; 4,432,755; 4,458,733; 4,898,209; 4,872,867; 3,826,260, and references cited therein.
Unfortunately, because all of these known methods require thorough reconstitution/mixing of the lyophilized product into the diluent prior to injection, they can typically involve lengthy procedures (in excess of 10 steps) in order to reconstitute the solid drug into a liquid formulation prior to administration. Such lengthy reconstitution steps can be complex, arduous and tedious for the patient and may render injection of the lyophilized product unfeasible. Moreover, these complicated procedures present risks of foaming, risk of contamination, and risk of accidental needle pricks. There clearly still exists a need for improved delivery devices and methods.
Co-pending U.S. patent application Ser. No. 11/172,064 ('064) provides an advancement in the technology and relates to a container closure assembly suitable for lyophilized pharmaceutical injectable products and designed to provide for direct injection of a lyophilized product without the need for a reconstitution/mixing/priming step of the powder and diluent prior to injection. The components of the disclosed container closure assembly were designed to function in a manufacturing function and an end user function and, upon completion of the lyophilization process, the assembly has minimal head space to avoid the need for priming. The disclosed container closure assembly is designed to utilize or be easily adaptable to industry standard or existing filling systems, thus providing a more economical alternative to prior art devices.
The present invention provides an improved alternative container closure design which facilitates the easy, direct injection of the lyophilized product without the need for a reconstitution/mixing/priming step of the powder and a liquid diluent by the end user. As with the assemblies described in the '064 application, the disclosed container closure assembly is designed to utilize or be easily adaptable to industry standard or existing filling systems, thus providing a more economical alternative to prior art devices.